An efficient synthesis of zolpidem

Full text of DOI:10.1080/00304948.2011.564558

This article was downloaded by: [University of Haifa Library]
On: 26 August 2013, At: 07:22
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/uopp20
An Efficient Synthesis of Zolpidem
a
a
a
Sachin S. Patil , Sachin V. Patil & Vivek D. Bobade
a
Department of Chemistry, HPT Arts and RYK Science College,
Nasik, India
Published online: 08 Apr 2011.
To cite this article: Sachin S. Patil , Sachin V. Patil & Vivek D. Bobade (2011) An Efficient Synthesis of
Zolpidem, Organic Preparations and Procedures International: The New Journal for Organic Synthesis,
43:2, 260-264, DOI: 10.1080/00304948.2011.564558
To link to this article: http://dx.doi.org/10.1080/00304948.2011.564558
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“
Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Organic Preparations and Procedures International, 43:260–264, 2011
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304948.2011.564558
An Efficient Synthesis of Zolpidem
Sachin S. Patil, Sachin V. Patil, and Vivek D. Bobade
Department of Chemistry, HPT Arts and RYK Science College, Nasik, India
Imidazo[1,2-a]pyridines (IPs) have received considerable attention because of their interest-
1
2
3,4
5,6
7
ing therapeutic properties, including antibacterial, antifungal, antiviral, antiulcer, and
8
anti-inflammatory behavior. They have also been identified as selective cyclin-dependent
9
10
11
kinase inhibitors, calcium channel blockers, β-amyloidal formation inhibitors, and
benzodiazepine receptor agonists,12 and constitute a novel class of orally active non-
peptidic bradykinin B2 receptor antagonists.1 Drug formulations containing imidazo[1,2-
a]pyridines such as alpidem (anxolytic), zolpidem (hypnotic), and zolimidine (antiulcer)
are currently marketed.
3
N
SO Me
2
N
Cl
Zolmidine
Cl
N
N
C
Me
N
N
N
Me
Cl
Me
Me
C
O
C H
3
7
N
O
C H
3
7
Zolpidem
Alpidem
Zolpidem (7) is a prescription medication used for the short-term treatment of insomnia,
as well as some brain disorders. It is a short-acting non-benzodiazepine hypnotic that
potentiates γ -aminobutyric acid (GABA), an inhibitory neurotransmitter, by binding to
14
GABAA receptors at the same location as benzodiazepines. Although its hypnotic effects
are similar to those drugs of the benzodiazepine class, it is molecularly distinct from
benzodiazepines and is classified as an imidazopyridine.
One reported synthesis1 of zolpidem proceeds in overall 19% yield from 2-bromo-
-methylacetophenone (1) as depicted in Scheme 1.
5,16
ꢀ
4
Submitted February 26, 2010.
Address correspondence to Vivek D. Bobade, Department of Chemistry, HPT Arts and RYK
Science College, Nasik, 422005, India. E-mail: v bobade31@rediffmail.com
260

An Efficient Synthesis of Zolpidem
261
O
N
N
CH Br
2
Me
a
Me
b
N
N
Me
Me
Me
NMe2
1
2
3
N
N
c
d
Me
Me
N
N
Me
Me
NMe2 I
CN
5
4
N
N
e
f
Me
Me
N
N
Me
Me
O
C
COOH
6
7
NMe2
(
a) 2-Amino-5-methylpyridine, EtOH, NaHCO
3
, ∆. (b) Acetic acid, aq. Dimethylamine,
I, ∆ (d) NaCN, EtOH, ∆ (e) KOH, EtOH /∆ (f)
formalin, RT (c) Acetone, CH
3
Carbonyldiimidazole, THF, dimethylamine / RT
Scheme 1
In a related procedure,17 an alternative preparation of 5 involves a Vilsmeier-Haack
formylation of 2 followed by sodium borohydride reduction of the aldehyde to the alcohol.
Tosylation of the alcohol and subsequent treatment with cyanide ion gave 5 30% yield
from 2.
Another literature method18,19 involved bromination of N,N-dimethyl-4-oxo-4-
tolylbutanamide (8) to 3-bromo-N,N-dimethyl-4-oxo-4-tolylbutanamide (9) followed by
condensation of resultant bromo derivative 9 with 2-amino-5-methylpyridine to give zolpi-
dem (7) in 17% yield (Scheme 2).
N
O
O
NMe2
NMe
2
b
Me
a
N
Me
O
O
Br
O
C
Me
Me
NMe2
8
9
7
(a) Bromine, acetic acid (b) 2-Amino-5-methylpyridine
Scheme 2
However, these procedures suffer from several disadvantages from a commercial pro-
duction standpoint such as (a) difficulty in handling the lachrymatory bromo compounds 1
and 9 on a large scale which requires precaution to avoid exposure, (b) multistep synthesis
for compound 6 as illustrated in Scheme 1 (3 steps from compound 3), (c) isolation (drying
operations) of intermediates such as compounds 1, 4 and 5 and the work-up procedures

262
Patil et al.
which lead to increased cycle time and hence increase in the manufacturing cost, (d) the
work-up procedure of the cyanation step is hazardous and requires safety measures as it
may contain residual cyanide (e) in the hydrolysis step (5 to 6), compound 2 is formed as
by-product (f) the use of carbonyldiimidazole (CDI) is expensive and is a highly moisture
sensitive reagent and the reaction does not proceed to completion (g) the low overall yields
in these procedures make them less viable for commercial production.
N
O
Me
O
NMe2
N
NMe2
Me
A or B
O
O
OTs
C
Me
Me N
Me
2
O
8
10
7
Method A: (i) HTIB, CH CN, reflux 2 h; (ii) 2-Amino-5-methylpyridine, reflux
3
Method B: (i) (PhIO) + p-TsOH/CH CN, reflux 2 h; (ii) 2-Amino-5-methypyridine, reflux
3
Scheme 3
We herein report a novel synthesis of zolpidem (7) by condensation of α-tosyloxyketone
0,20 prepared in situ by reaction of N,N-dimethyl-4-oxo-4-tolylbutanamide 8 and [hy-
droxy(tosyloxy)iodo]benzene (HTIB), with 2-amino-5-methylpyridine to give zolpidem
Method A). [Hydroxy(tosyloxy)iodo]benzene (HTIB), known as Koser’s reagent has been
1
(
gaining increasing popularity as versatile reagent for the preparation of α-tosyloxy ketones
from enolizable ketones.2
1–23
We also established that it is possible to use a combination
of iodosobenzene and p-toluenesulfonic acid [(PhIO)n + p-TsOH] in place of HTIB. This
combination reagent generates HTIB in situ, which then reacts with ketone 8 to give the
intermediary α-tosyloxyketone 10 (Method B) which further reacted in situ with 2-amino-
5
-methylpyridine to give zolpidem; however, the overall yield in this method was less than
that of Method A.
In conclusion this investigation describes a simple and efficient one-pot procedure for
the synthesis of zolpidem under mild conditions.
Experimental Section
Melting points are uncorrected and were determined on a Buchi Melting Point apparatus.
1
H NMR spectra were obtained in CDCl3 using TMS as internal standard on Brucker
spectrometer at 300MHz. Mass spectra were recorded on Shimadzu LCMS-QP8000, LC-
MS and AB-4000 Q-trap LC-MS/MS. The elemental analysis was performed on Perkin-
Elmer model 2400 CHNS/O analyzer. The reaction was monitored by TLC on silica gel
plates.

An Efficient Synthesis of Zolpidem
263
Procedure for the Synthesis of Zolpidem
Method A
A solution of N,N-dimethyl-4-oxo-4-tolylbutanamide (8, 2.19 g, 1.0 mmol)24 and hy-
droxy(tosyloxy)iodo]benzene (HTIB) (3.98 g, 1.0 mmol) in acetonitrile (25 mL) was re-
fluxed for 2 hrs. After the completion of reaction, as monitored on TLC (EtOAc:hexane,
80:20), 2-amino-5-methylpyridine (1.1 g, 1.0 mmol) was added to the reaction mixture
which was further refluxed for 2h. After completion of reaction as indicated by TLC, (sol-
vent system CHCl3:methanol 9:1) acetonitrile was distilled off. The residue was dissolved
in dichloromethane (25 mL) and washed with a 5% aqueous sodium carbonate (20 mL) and
water (20 mL). The organic phase was dried over MgSO4, concentrated in vacuo and the
◦
solid residue was crystallized from toluene, dried at 50 C under vacuum, to yield zolpidem
◦
15
◦
as a yellow solid (1.84 g, 60%) mp.192–194 C, lit. mp. 194–195 C.
Method B
A solution of iodosobenzene (2.20 g, 10 mmol), p-toluenesulfonic acid (1.72 g, 10 mmol)
in acetonitrile (20 mL) was stirred at room temperature for 5 min and N,N-diethyl-4-oxo-4-
tolylbutanamide (2.19 g, 1.0 mmol) was added and the mixture was refluxed for 2h. To this
solution, 2-amino-5-methylpyridine (1.1g, 1.0 mmol) was added and the resulting mixture
was further refluxed for 2 hrs. The product was isolated (1.44 g, 47%) as described in the
procedure given in Method A.
1H NMR (CDCl3): δ 2.25 (s, 3H, ArCH3), 2.34 (s, 3H, ArCH3), 2.85 (s, 3H, NCH3),
2
8
1
.94 (s, 3H, NCH3), 4.16 (s, 2H, COCH2), 7.05 (d, 2H, ArH), 7.43–7.66 (m, 4H, ArH),
13
.11 (s, 1H, ArH); C NMR (CDCl3): δ 17.92, 20.79, 29.31, 35.34, 37.03, 113.79, 115.37,
+
21.82, 130.26, 137.27, 142.11, 142.81, 167.63. MS: M 308, 235, 219, 92
Anal. Calcd. For C19H21N3O: C, 74.25; H, 6.88; N, 13.67; Found: C, 74.10; H, 6.74;
N, 13.79.
Acknowledgement
The authors thank the University Grants Commission, New Delhi for financial assistance.
They also thank IIT Mumbai Department of Chemistry for providing spectral data analyses.
The author is also grateful to Mr. Omkar Herlekar, Director of Omkar Chemical Pvt. Ltd,
Ambernath, for providing gift sample of diacetoxyiodobenzene (DIB) and iodosobenzene.
References
1
2
3
4
5
. A. R. Katritzky, Y.-J. Xu and H. Tu, J. Org. Chem., 68, 4935 (2003).
. Y. Rival, G. Grassy and G. Michel, Chem. Pharm. Bull., 40, 1170 (1992).
. M. H. Fisher and A. J. Lusi, Med. Chem., 15, 982, (1972).
. Y. Rival, G. Grassy, A. Taudou and R. Ecalle, Eur. J. Med. Chem., 26, 13 (1991).
. C. Hamdouchi, J. de Blas, M. del Prado, J. Gruber, B. A. Heinz and L. Vance, J. Med. Chem.,
42, 50, (1999).

264
Patil et al.
6
. M. Lhassani, O. Chavignon, J.- M. Chezal, J.-C. Teulade, J.-P. Chapat, R. Snoeck, G. Andrei, J.
Balzarini, E. De Clercq and A. Gueiffier, Eur. J. Med. Chem., 34, 271 (1999).
7
. J. J. Kaminsky and A. M. Doweyko, J. Med. Chem., 40, 427, (1999).
8
. K. C. Rupert, J. R. Henry,, J. H. Dodd, S. A. Wadsworth, D. E. Cavender, G. C. Olini, B. Fahmy
and J. Siekierka, Bioorg. Med. Chem. Lett., 13, 347 (2003).
9
. C. Hamdouchi, B. Zhong, J. Mendoza, E. Collins, C. Jaramillo, J. E. De Diego, D. Robertson, C.
D. Spencer, B. D. Anderson, S. A. Watkins, F. Zhanga and H. B. Brooks, Bioorg. Med. Chem.
Lett., 15, 1943 (2005).
1
1
0. P. J. Sanfilippo, M. Urbanski, J. B. Press, B. Dubinsky and J. B. Moore, J. Med. Chem., 34, 2060
1991).
(
1. S. C. Goodacre, L. J. Street, D. J. Hallett, J.M. S. Crawforth-Kelly, A. P. Owens, W. P. Blackaby,
R. T. Lewis, J. Stanley, A. J. Smith, P. Ferris, B. Sohal, S. M. Cook, A. Pike, N. Brown, K. A.
Wafford, G. Marshall, J. L. Castro and J. R. Atack, J. Med. Chem., 49, 35 (2006).
12. G. Trapani, M. Franco, L. Ricciardi, A. Latrofa, G. Genchi, E. Sanna, F. Tuveri, E. Cagetti, G.
Biggio and G. Liso, J. Med. Chem., 40, 3109 (1997).
13. Y. Abe, H. Kayakiri, S. Satoh, T. Inoue, Y. Sawada, K. Imai, N. Inamura, M. Asano, C. Hatori,
A. Katayama, T. Oku, and H. Tanaka, J. Med. Chem., 41, 564 (1998).
1
1
1
4. B. Lemmer, Physiol. Behav., 90, 285 (2007).
5. K. Jean-Pierre, US Patent 4382938 (1983); Chem. Abstr., 97, 92280v (1982).
6. A. M. Jasty, R. R. Tamma, S. Mohanarangam, S. Yasareni, G. S. Rupakala and G. Debashish,
US Patent 2007/0027180 (2007); Chem. Abstr., 146, 206303t (2007).
1
1
1
7. K. Jean-Pierre, G. Pascal and B. Jean-Michel, EP Patent 92,459 (1983); Chem. Abstr., 100,
1
39102m (1984).
8. S. Markus and W. Wolfgang, US Patent 2002/0183522 (2002); Chem. Abstr., 136, 102382v
(2002).
9. G. Trapani, M. Franco, L. Ricciardi, A. Latrofa, G. Genchi, E. Sanna, F. Tuveri, E. Cagetti, G.
Biggio and G. Liso, J. Med. Chem., 40, 3109 (1997).
2
2
2
2
0. Compound 10 was not isolated, but treated in situ with 2-amino-5-methylpyridine.
1. O. Prakash, K. Pannu, R. Prakash and A. Batra, Molecule, 11, 523 (2006).
2. P. F. Zhang and Z. C. Chen, Synthesis, 2075 (2001).
3. R. Agrawal, R. Pundeer, V. Kumar, V. Chaudhri, S. P. Singh and O. Prakash, Synth. Commun.,
24, 2659 (2004).
24. For the preparation of N,N-dimethyl-4-oxo-4-tolylbutanamide, see Y. Kumar, M. Prasad and A.
NathWO02/18303 (2002); Chem. Abstr., 136, 2165399g (2002).